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History of Biogenic Amine Use for Treating Obesity

The discovery of ephedrine (Product No. E2750) in the 1930s led to the synthesis of amphetamines. Initially utilized as stimulants, they were soon shown to exhibit food intake and appetite suppressing qualities. Because of the abuse potential of the amphetamines, other drugs were sought and synthesized in the 1960s, including phentermine (Product No. P8653) and mazindol (Product No. M2017), both of which block the reuptake of norepinephrine (Product No. A7257) in the hypothalamus.

Although less abused, these drugs still possessed stimulant properties leading to the synthesis of fenfluramine (Product No. F8507). Although similar in structure to the amphetamines, it demonstrated no stimulant activity. Fenfluramine also inhibited serotonin (Product No. H9523) reuptake in presynaptic neurons within the paraventricular nucleus of the hypothalamus1. Dexfenfluramine (Product No. F112), the active isomer of fenfluramine, was developed in the 1970s after it was shown to be more potent and selective than the racemic compound. The FDA approved dexfenfluramine in 1996 for weight loss maintenance. However, both dexfenfluramine and fenfluramine were voluntarily withdrawn in 1997 when patients receiving either compound or a combination therapy of dexfenfluramine and phentermine (Fen-Phen) developed cardiac valvular disease1. Other potential therapies have also proven disappointing. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Product No. F132), fluvoxamine (Product No. F2802) and sertraline, originally developed to treat depression, were evaluated as anti-obesity therapies. Although these drugs initially produced weight loss, significant weight regain occurred despite continued administration of the drugs1. In addition, the FDA has recently requested that norephedrine (Product No. P7876) be removed from all drug products due to the risk of hemorrhagic stroke1. Ephedrine has also been removed as an over-the-counter weight loss remedy due to deleterious side effects.

Since many obese individuals are more likely to suffer from heart disease and hypertension, the development of thermogenic drugs, which increase metabolic rates safely without increasing heart rate or blood pressure, has proven difficult. Atypical adrenoceptors, termed β3-adrenoceptors, mediate the thermogenic effects of sympathomimetic agents without producing the typical β1- and β2-adrenoceptor responses of cardiac stimulation or smooth muscle contraction1. Serotonin acts as another metabolic signal by regulating POMC neurons in the ARC. 5-HT2C serotonin receptor activation causes weight loss while receptor deletion causes adult-onset obesity in mice2. Although none have proven successful, the development of β3-adrenoceptor or 5-HT2C serotonin receptor agonists as anti-obesity treatments still holds promise.